Gut brain axis

expression and results in activation of sympathetic preganglionic neurons projecting the brain stem and spinal cord. Leptin also inhibits NPY neurons in ARC, and activates the ventro- and dorsomedial hypothalamic projection of PVN [66].

1.5. Effect of stress on gastrointestinal tract (GI)

It is well known, that symptoms of different GI disorders worsen in prolonged stress and negative emotions. Activation of HPA axis and sympathoadrenal system alter various physiological functions of GI such as gastric secretion, gut motility, visceral sensitivity, mucosal blood flow, barrier function and triggers different gastrointestinal relevant symptoms like dyspepsia, diarrhoea or abdominal pain. Chronic activation of the stress system can lead to severe GI disorders such as irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). Enteric nervous system (ENS) plays an essential role in the regulation of gut functions. It has a great impact on motility and secretion of GI neuropeptides and hormones. Strong evidences confirm that, prolonged stress as well as early life stress are able to alter central pain circuitry, influence motility and permeability through GI [67, 68].

In the last decade, emerging studies demonstrated important interaction between the gut microbiome and host. Stress induces a notable shift in the composition of microbiota, with the growth of pathogenic bacteria and this alteration further aggravate the symptoms of GI disorders. For example, norepinephrine enhances the virulence of E. coli or C. jejuni [67, 68]. Infants with altered microbiota composition showed higher level of infant GI symptoms and allergic reactions.

The gut microbiome able to modify the interaction between HPA axis and immune system. Stress increases gut permeability and results in “leaky gut” which underpins chronic low-grade inflammation, due to the elevated plasma level of bacterial lipopolysaccharide (LPS) [69]. CRF, which is also produced within the gut, plays an essential role in the stress-induced gut permeability dysfunction, modulation of inflammation in gut, and contributes to visceral hypersensitivity via CRF receptors. Of note, early life stress causes elevated plasma corticosterone level and results in increased gut permeability and bacterial translocation to spleen and liver [69].

1.6. Gut brain axis

The microbiome is a complex and dynamic mixture of microorganisms, which includes different bacteria, fungi, archaea and viruses [70]. These microbial communities

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present in different parts of the human body such as the oro-naso-pharyngeal cavity, skin, vagina, gastrointestinal tract etc. These communities interact with host and influence health and disease [71]. The largest proportion of the microbiome is found in the gastrointestinal tract: from the stomach to the colon, bacterial biomass ranges from 10^2–3 to 10¹¹–10¹² cells/ml, among those approximately 95% being anaerobic [70]. The human gut microbiome consists of seven major phyla: Bacteroidetes, Actinobacteria, Cyanobacteria, Fusobacteria, Proteobacteria, and Verrucomicrobia [72]. The microbiome is exposed to different factors, which constantly change the composition of it. These factors include many variables such as birth, breast feeding, diet, stress, aging, drugs (antibiotics) etc. [73-75].

Gut microbiome widely interacts with the host’s metabolic system (Fig.3.). The dietary ingredients can be metabolized differentially and it highly depend on the composition of microbiome. For instance, different bacteria can produce bile acid, short chain fatty acids (SCFA), choline etc. [69, 76]. SCFAs suppress histone deacetylases and able to modify intracellular signalling through their specific receptors that found throughout the body.

For instance, propionic acid mediates advantageous effect on the regulation of body weight and glucose metabolism by influencing FFAR3 receptor containing nerve fibres in hepatic portal vein [77]. Recent studies indicate that microbiome is able to influence enteroendocrine cells in gut. E. coli produced proteins are able to induce secretion of GLP-1 and PYY hormones from enteroendocrine cells that affect food intake [78]. For these reason, microbiome can contribute to the development of different metabolic system-related disorders such as, obesity or diabetes [79, 80].

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Figure 3. Schematic representation of different pathways of gut brain axis [81].

It is also well documented that a shift in gut microbiome can be associated with gastrointestinal disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). A recent study identified key bacterial species that may be involved in the development of these gastrointestinal diseases and altering the gut microbiota has been proposed as a strategy for the treatment [82].

Growing body of evidence indicates dysbiosis of gut microbiota could contribute or, exaggerate several neuropsychiatric disorders such as anxiety, depression, Alzheimer disease, Parkinson disease, multiple sclerosis, autism etc. [75]. There are many different pathways, through which, microbiome can influence the normal function of brain.

Recently, a number of microbial metabolites (referred to as neuro-active metabolites) produced through tryptophan metabolism have been suggested to influence the gut brain-axis. Interestingly, germ free mice have elevated level of circulating tryptophan beside lower level of 5-HT compared to conventionally colonized mice. Another study indicated that probiotic administration of Lactobacillus decreased the colonic tryptophan degradation by inhibiting indoleamine 2,3 dioxygenase (IDO – rate limiting enzyme of kynurenine pathways) [83]. Besides that, many microbes can metabolize

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neurometabolites such as GABA, noradrenaline, serotonin, dopamine, acetylcholine, tryptophan that could directly affect brain functions [76]. In addition, gram-negative bacteria induce pro-inflammatory cytokines by their cell wall component, LPS; which stimulates toll- like receptor (TLR) coupled immunological pathways. Inflammatory mediators can also access to the brain. For instance, Campylobacter jejuni infection triggers neuronal activity in the vagal sensory ganglia and in the NTS. The vagus nerve has also an important role in the mediation of gut-brain communication. There are strong evidences, which demonstrate that microbiome is capable to alter the activity of vagal projection. Administration of Lactobacillus reuteri supported wound healing in mice by enhanced oxytocin secretion in hypothalamus, which was eliminated by vagotomy.

Another experiment showed that administration of Lactobacillus rhamnosus induced anxiolytic and antidepressant-like behaviour, however, this effect was attenuated in vagotomized mice [69, 76].